Histone deacetylase (hereinafter also referred to as HDAC) is known to play an essential role in the transcriptional machinery for regulating gene expression, induce histone hyperacetylation and to affect the gene expression. Therefore, it is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors, etc.
Many compounds which can inhibit the functions of the enzymes (HDAC inhibitors) has been studied extensively (see, e.g., WO01/38322, WO02/22577, WO2004/024160, US2004/0087631, WO2004/063169, US2004/0092558, WO2005/086898 etc).
For example, WO 01/38322 discloses an inhibitor of histone deacetylase represented by the following formula:Cy-L1-Ar—Y1—C(O)—NH—ZwhereinCy is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted;L1 is —(CH2)m—W— wherein m is an integer of 0 to 4, and W is selected from the group consisting of —C(O)NH—, —S(O)2NH—, etc.;Ar is optionally substituted arylene, which is optionally fused to an aryl, heteroaryl ring, etc.;Y1 is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene is optionally substituted; andZ is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl and —O-M wherein M is H or a pharmaceutically acceptable cation.
WO 02/22577 discloses the following hydroxamate compound as a deacetylase inhibitor:
whereinR1 is H, halo or a straight chain C1-C6 alkyl;R2 is selected from H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, etc.;R3 and R4 are the same or different and independently H, C1-C6 alkyl, acyl or acylamino, orR3 and R4 together with the carbon to which they are bound to represent C═O, C═S, etc., orR2 together with the nitrogen to which it is bound and R3 together with the carbon to which it is bound to form a C4-C9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;R5 is selected from H, C1-C6 alkyl, etc.;n, n1, n2 and n3 are the same or different and independently selected from 0-6, when n1 is 1-6, each carbon atom can be optionally and independently substituted with R3 and/or R4;X and Y are the same or different and independently selected from H, halo, C1-C4 alkyl, etc.;or a pharmaceutically acceptable salt thereof.